A wide range of naphthoquinones are known in the art. Such compounds have been variously described as having antimalarial, anticoccidial and antitheilerial activity. Some compounds have also been described as possessing activity against external parasites. Thus, Fieser et al, J. Amer. Chem. Soc. 1948, 70, 3156-3165 (and references cited therein) describe a large number of 2-substituted-3-hydroxy-1,4-naphthoquinones as having antimalarial activity. A number of these compounds have also been described in U.S. Pat. Nos. 2,553,647 and 2,553,648. Further classes of 2-substituted-3-hydroxy-1,4-naphthoquinones having activity as antimalarial, anticoccidial and/or antitheilerial agents are described in U.S. Pat. Nos. 3,367,830, and 3,347,742, U.K. Patent Specification No. 1553424, and European Patent Specifications Nos. 2228, 77551, 77550 and 123,238.
European Patent No. 123,238 discloses 2-substituted-3-hydroxy-1,4-naphthoquinones which are said to be active against the human malaria parasite Plasmodium falciparum and also against Eimeria species such as E. tenella and E. acervulina, which are causative organisms of coccidiosis. 2-Substituted-3-hydroxy-1,4-naphthoquinones (1) have been described in literature as possessing anti-protozoal activity, in particular anti-malarial. Anti-coccicidal activity has also been reported to a lesser extent. Hundreds of such compounds as possessing anti-malarial activity have been disclosed by Fieser and co-workers.
Many orally administered drugs display poor bio-availability when administered in conventional dosage forms. With several drugs, absorption may be as little as 30 per cent or less of the orally administered dose. To compensate for this effect, a very large dose is often administered so that absorption of the therapeutically required quantity of the drug can occur. This technique is costly with expensive drugs, and the non-absorbed drug may also have undesirable side effects within the gastrointestinal tract. In addition, the poorly absorbed drugs often display a great deal of variability between patients in bioavailability, and this can create dosing problems. This poor bioavailability is often associated with poor solubility of drugs. There are various techniques available to overcome solubility and bioavailability problem, and one such viable technique is particle size reduction. However particle size reduction adds another step to the process as well as added cost. Another approach to improving poor bioavailability by raising aqueous solubility of the drug is administering a prodrug. Any compound metabolized in vivo to provide the bioactive agent is a prodrug. Prodrugs are therapeutic agents, inactive per se, but transformed into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations
Atovaquone has low oral bioavailability, which has been partly attributed to poor water solubility. It has also shown that an oral dosing of atovaquone has been complicated by variable plasma atovaquone levels, which were an important determinant of therapeutic outcome. In clinical trial with a conventional tablet formulation, it was observed that a therapeutic response against Pneumocystis carinii Pneumonia depended on steady-state levels in plasma. In order to overcome the problems associated with poor solubility and variable plasma atovaquone levels, prior art has used atovaquone of small particle size or has made atovaquone derivatives which may act like prodrugs of the same.
U.S. Pat. No. 6,649,659 relates to a process for the production of microfluidized particles of atovaquone having improved bioavailability. The patent discloses that microfluidised particles of atovaquone produced using a Microfluidiser, surprisingly, had improved bioavailability of the compound. The patent also provides small particles of atovaquone, wherein suitably at least 90% of the particles have a volume diameter in the range of 0.1-3 μm. Preferably at least 95% of the particles have a volume diameter in the range 0.1-2 μm.
Hage et al., European Journal of Medicinal Chemistry, 44(11), 4778-4782 (2009) discloses the synthesis and antimalarial activity of new atovaquone derivatives were designed which was substituted at the 3-hydroxy group by ester and ether functions. The compounds were evaluated in vitro for their activity against the growth of Plasmodium falciparum, the malaria causing parasite. All the compounds showed potent activity, with IC50 values in the range of 1.25-50 nM, comparable to those of atovaquone and much higher than chloroquine or quinine.
Comley et al., Antimicrobial agent and Chemotherapy, 39, 2217-2219 (1995) states the prophylactic efficacy of 17C91, a carbamate prodrug of Atovaquone was investigated in a severe combined immunodeficient mouse model of Pneumocystis carinii pneumonia (PCP). At an oral dosage equivalent to 100 mg of Atovaquone per Kg of body weight per day, 17C91 protected 9 of 10 mice from PCP and had a Prophylactic efficacy comparable to that of co-trimoxazole (at 250 mg of sulfamethoxazole plus 50 mg of trimethoprim per kg per day orally). The intensity of P. carinii infection (infection score) of mice treated with 17C91 correlated with the concentration of Atovaquone in the plasma, with clearance of the infection associated with plasma Atovaquone levels of >35 μ/ml. 17C91 given orally provided enhance levels of Atovaquone in the plasma compared with the conventional Atovaquone formulation. Additional studies reported in this paper demonstrate that the Prophylactic activity 17C91 against PCP in severe combined immunodeficient mice is comparable to that of a new oral microparticulate formulation of Atovaquone.
Karaman et al., Chem Biol Drug Des, 76, 350-360 (2010) discloses computer-assisted design of Pro-drugs for antimalarial atovaquone, the density functional theory (DFT) and ab initio calculation results for the proton transfer reaction in Kirby's enzyme models 1-6 reveal that the reaction rate is largely dependent on the existence of a hydrogen bonding net in the reactants and the corresponding transition states. Further, the distance between the two reacting centers and the angle of the hydrogen bonding formed along the reaction path has profound effects on the rate. Hence, the study on the system reported herein could provide a good basis for designing antimalarial (Atovaquone) prodrug system that can be used to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for prodrug 1Pro may be predicted to be about 1011 times faster than that for a prodrug 4Pro and about 104 times faster than prodrug 2Pro: rate1Pro>rate2Pro>rate4Pro. Thus, the rate by which the prodrug releases the antimalarial drug can be determined according to the nature of the linker.
The present inventors have now found a new compound as a prodrug of Atovaquone, in order to overcome the problems associated with solubility and variable bioavailability of atovaquone. The Atovaquone prodrug of the present invention is expected to provide better solubility than atovaquone and non-variable plasma levels of atovaquone as compared to the levels obtained after administration of atovaquone.
We have synthesized a compound of formula (I) i.e., 3-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyloxy-2-trans-[(4-chlorophenyl)cyclohexyl][1,4] naphthaquinone by using atovaquone (II) and 5-methyl-4-chloromethyl dioxalone (III) using the route shown in Scheme 1.

